1. Technical Field
The present invention is concerned with delivering a pharmaceutical composition to the brain of a mammalian subject for treating brain diseases and disorders. The process includes providing a dispersion of the pharmaceutical composition as particles and administering the dispersion to the mammalian subject for delivery to the brain of a portion of the pharmaceutical composition by cells capable of reaching the brain. The present invention further contemplates intracellular uptake of the dispersion of the pharmaceutical composition as particles by the cells prior to administration into the mammalian subject. The process of uptake of the particles by the cells can occur, for example, through phagocytosis or adsorption.
2. Background Art
Drugs or pharmaceutical agents that are used to treat brain disorders or diseases are usually administered orally. However, most of the ingested drug does not target the brain and is, instead, metabolized by the liver. This inefficient utilization of drug may require ingestion of higher drug concentrations that can produce toxic effects such as, for example, cardiotoxicity, hepatotoxicity and nephotoxicity. Furthermore, lower amounts of drugs are able to reach the brain thereby requiring an increased frequency of doses. More efficient use of the drug can be realized both by eliminating liver metabolism and directly targeting the brain.
Many therapeutic or diagnostic agents are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges to delivering them orally or parenterally. Compounds that are insoluble in water can have significant benefits when formulated as a stable suspension of sub-micron particles. Accurate control of particle size is essential for safe and efficacious use of these formulations. Particles must be less than seven microns in diameter to safely pass through capillaries without causing emboli (Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981). One solution to this problem is the production of small particles of the insoluble drug candidate and the creation of a microparticulate or nanoparticulate suspension. In this way, drugs that were previously unable to be formulated in an aqueous system can be made suitable for intravenous administration. Suitability for intravenous administration includes small particle size (<7 μm), low toxicity (as from toxic formulation components or residual solvents), and bioavailability of the drug particles after administration.
Bender et al. disclose the treatment of HIV-infected monocytes/macrophages with polyhexylcyanoacrylate nanoparticles loaded with either the nucleoside analog zalcitabine (2′,3′-dideoxycytidine), or saquinavir, a protease inhibitor (Bender et al., Efficiency of Nanoparticles as a Carrier System for Antiviral Agents in Human Immunodeficiency Virus-Infected Human Monocytes/Macrophases In Vitro, Antimicrobial Agents and Chemotherapy, June 1996, volume 40(6), p. 1467-1471). The polyhexylcyanoacrylate nanoparticles were prepared by emulsion polymerization and tested in-vitro for antiviral activity in primary human monocytes/macrophages. An aqueous solution of saquinavir showed little antiviral activity in HIV-infected macrophages, whereas the nanoparticulate formulation demonstrated significant antiviral activity at one-tenth the solution concentration. At a concentration of 100 nM, saquinavir in solution was completely inactive in chronically HIV-infected macrophages, but when bound to nanoparticles it caused a 35% decrease in viral antigen production. In this study, the drug was entrained in a polymer (polyhexylcyanoacrylate) matrix. The idea of preparing pure, solid drug nanoparticles for delivery to macrophages was not disclosed. Particles were only delivered to macrophages in-vitro and did not contemplate drug delivery by administering nanoparticle-treated cells that are capable of reaching the brain to transport the drug. Von Briesen discloses the phagocytozation of nanoparticles of entrained in polymers (e.g., polyhexylcyanoacrylate) by monocytes/macrophages (H. von Briesen, Controlled Release of Antiretroviral Drugs, AIDS Rev, 2000, volume 2, pages 31-38.
U.S. Pat. No. 4,973,465 (Baurain et al.) and U.S. Pat. No. 5,100,591 (Leclef et al.) discloses lipid microparticles of nystatin, amphoterin B and other anti-fungal compounds, potentially having enhanced targeting for macrophages.
The present invention provides a solution to effective dosing to the brain and associated neuronal tissues. The present invention involves delivering a drug by using cells that are capable of reaching the brain to transport the drug. For example, one particular mode of delivery involves utilizing macrophages present in the patient's cerebrospinal fluid (CSF) to deliver drugs to the brain. This process requires that the pharmaceutical composition is in a particulate form that readily permits macrophage uptake by phagocytosis.